Solid organ and bone marrow transplantation (BMT)represent the last hope for many patients with terminal organ failure, and non-malignant as well as malignant bone marrow disease. Significant barriers to these procedures exist, which limit the clinical applicability. One of the most substantial barriers is the fact that true immunologic tolerance to either a solid organ or bone marrow allograft is not yet achievable in the clinical setting. Patients, therefore, are at constant risk of acute and chronic rejection, and in the case of BMT, of graft-versus-host disease. To treat or prevent these complications, transplant patients require long- term non-specific immunosuppression, which plagues patients with infectious, cardiovascular and malignant sequelae. Thus, strategies to promote the acceptance of allogeneic tissues without the need for chronic immunosuppression will reduce the risk of these life- and graft-threatening complications and expand the application of transplantation. Much work has focused on the role that T cells play in transplantation tolerance, and strategies have been devised to down-regulate T cell activity by inhibiting T cell costimulation. However, these strategies have not yet been clinically successful, which has promted a search for mediators of T cell costimulation blockade-resistant rejection'. It is increasingly recognized that Natural Killer (NK) cells impact transplantation success, and may represent a potent barrier to costimulation blockade-induced tolerance. The mechanisms by which they do this are currently unknown. This research proposal is designed to elucidate the mechanisms underlying NK alloreactivity through the following Specific Aims: 1) To define the molecular mechanisms of NK cell-mediated rejection of allo-BMT in the presence and absence of T cell costimulation blockade. 2) To determine the effect of specific inhibition of NK-mediated adhesion and activation on rejection of allo-BMT during costimulation blockade transplantation. The research proposed is part of a customized 4-year tranining and career development plan for the PI. The proposal includes active mentoring by experienced scientists, access to diverse resources, and an environment uniquely suited to help the PI develop as an independent clinician-scientist. Relevance: Each year in the US more than 35,000 children and adults receive bone marrow and solid organ transplants, and over 10,000 people die while awaiting a suitable donor. Thus, complications of transplantation represent a major public health issue.